Department of Neurology and Weill Institute for Neurosciences, University of California at San Francisco, San Francisco, CA, 94158, USA.
Department of Neurology and Weill Institute for Neurosciences, University of California at San Francisco, San Francisco, CA, 94158, USA.
J Autoimmun. 2019 Jul;101:56-69. doi: 10.1016/j.jaut.2019.04.003. Epub 2019 Apr 19.
The molecular events underlying the transition from initial inflammatory flares to the progressive phase of multiple sclerosis (MS) remain poorly understood. Here, we report that the microtubule-associated protein (MAP) Tau exerts a gender-specific protective function on disease progression in the MS model experimental autoimmune encephalomyelitis (EAE). A detailed investigation of the autoimmune response in Tau-deficient mice excluded a strong immunoregulatory role for Tau, suggesting that its beneficial effects are presumably exerted within the central nervous system (CNS). Spinal cord transcriptomic data show increased synaptic dysfunctions and alterations in the NF-kB activation pathway upon EAE in Tau-deficient mice as compared to wildtype animals. We also performed the first comprehensive characterization of Tau post-translational modifications (PTMs) in the nervous system upon EAE. We report that the methylation levels of the conserved lysine residue K306 are significantly decreased in the chronic phase of the disease. By combining biochemical assays and molecular dynamics (MD) simulations, we demonstrate that methylation at K306 decreases the affinity of Tau for the microtubule network. Thus, the down-regulation of this PTM might represent a homeostatic response to enhance axonal stability against an autoimmune CNS insult. The results, altogether, position Tau as key mediator between the inflammatory processes and neurodegeneration that seems to unify many CNS diseases.
多发性硬化症（MS）从初始炎症发作向进展阶段的转变的潜在分子事件仍知之甚少。在这里，我们报告微管相关蛋白（MAP）Tau 在 MS 模型实验性自身免疫性脑脊髓炎（EAE）的疾病进展中发挥性别特异性的保护作用。对 Tau 缺陷型小鼠的自身免疫反应的详细研究排除了 Tau 的强烈免疫调节作用，这表明其有益作用可能在中枢神经系统（CNS）内发挥。脊髓转录组数据显示，与野生型动物相比，Tau 缺陷型小鼠在 EAE 中突触功能障碍增加和 NF-kB 激活途径改变。我们还首次对 EAE 时神经系统中 Tau 的翻译后修饰（PTMs）进行了全面表征。我们报告说，在疾病的慢性期，保守赖氨酸残基 K306 的甲基化水平显著降低。通过结合生化测定和分子动力学（MD）模拟，我们证明 K306 处的甲基化降低了 Tau 与微管网络的亲和力。因此，这种 PTM 的下调可能代表一种针对自身免疫性中枢神经系统损伤增强轴突稳定性的体内平衡反应。总之，这些结果将 Tau 定位为炎症过程和神经退行性变之间的关键介质，似乎将许多中枢神经系统疾病统一起来。
